1. Field of the Invention
The present invention relates to quinoline derivatives and quinazoline derivatives which have antitumor activity. More particularly, the present invention relates to quinoline derivatives and quinazoline derivatives which have inhibitory activity against the autophosphorylation of fibroblast growth factor receptors and have inhibitory activity against abnormal cell proliferation.
2. Background Art
Growth factors such as epithelial growth factors, platelet-derived growth factors, insulin-like growth factors, and basic fibroblast growth factors (hereinafter abbreviated to “bFGF”) play an important role in cell proliferation. Among others, bFGF is known to accelerate cell proliferation and migration of vascular endothelial cells, fibloblasts and the like, and is also known to be involved in angiogenesis and wound healing (Trends. Pharmacol. Sci. April; 22 (4): 201–7, 2001).
Further, the expression of bFGF, or FGFR1 (hereinafter referred to as “Flg”), FGFR2 (hereinafter referred to as “Bek”) and the like belonging to a fibroblast growth factor receptor family is reported to be found in various cancers such as brain tumors, lung cancer, breast cancer, gastric cancer, head and neck cancer, and prostatic cancer (Proc. Natl. Acad. Sci. USA, 87: 5710–5714, 1990 Oncogene. 1997 Aug. 14; 15 (7): 817–26 Cancer Res. 1994 Jan. 15; 54 (2): 523–30. Cancer Res. 1992 Feb. 1; 52 (3): 571–7). In particular, it is reported for gastric cancer that overexpression of Bek correlates with poor prognosis mainly in poorly differentiated cancers such as scirrhus gastric cancers (Clin Cancer Res. 1996 August; 2 (8): 1373–81. J Cancer Res Clin Oncol. 2001 April; 127 (4): 207–16. Int Rev Cytol. 2001; 204: 49–95.).
There is a plurality of reports on small molecule compounds having inhibitory activity against the autophosphorylation of Flg (J Pharmacol Exp Ther. 1998 July; 286 (1): 569–77. Invest New Drugs. 1999; 17 (2): 121–35. Cancer Res. 2001 Feb. 15; 61 (4): 1464–8.). On the other hand, there is no report on compounds capable of inhibiting the autophosphorylation of Bek which is considered to be deeply involved in the progression of gastric cancer.